Allergic reactions involved in allergic diseases, for example, some types of bronchial asthma, conjunctivitis, rhinitis, dermatis, and hypersensitivity are caused by the release of various chemical mediators such as histamine, prostaglandin, leukotriene, thromboxane, and platelet activating factor from mast cells or basophils upon binding of the particular antigen with IgE antibody on the surface of such cells. Various symptoms are induced by such allergic reactions, and nosotropic therapies are most commonly employed to relieve such symptoms. Etiotropic therapies are also popular that employ compounds such as sodium cromoglicate, tranilast, ketotifen, and azelastine, that are capable of inhibiting the release of chemical mediators among the series of allergic reactions. However, compounds that are capable of blocking the stage of reactions preceding the release of chemical mediators are scarcely known, and the development of such compounds useful for pharmaceutical composition is sincerely awaited. In view of such conditions, a compound capable of inhibiting the production of IgE antibody, that is responsible for various allergic diseases as mentioned above, would be highly useful as a therapeutic agent to enable the more etiotropic treatment of such diseases.
Prior arts relating to the compound of the present invention are hereinafter described.
U.S. Pat. No. 3,200,123 discloses 2-substituted-5,6-dihydroimidazo[ij]quinoline derivatives having an inflammatory activity without any pharmacological data. intensity and detailed mechanism of such activity of the individual compound are unknown. In Journal of Organic Chemistry, 25, 1138-1147, 1960, the inventors of the U.S. Pat. No. 3,200,123 reported that only some compounds among the above-mentioned dihydroimidazo[ij]quinoline derivatives proved effective in animals with dextran sulfate-induced edema. Both prior art documents fail to indicate anti-allergic activities, in particular, the activity to suppress IgE antibody production.
Some 1-substituted-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinoline derivatives are reported in Bulletin of the Chemical Society of Japan, 61, 423-429, 1988. These compounds are intermediate products in the synthesis of 3-phenyl-4H-benzo[hi]pyrrolo[2,1,5-cd]indolizine-4-one compounds, whose electronic features are of engineering interest. This document does not at all disclose pharmacological activities.
Chemical and Pharmaceutical Bulletin, 34, 2435-2442, 1986 discloses tricyclic and tetracyclic indolizine compounds having anti-allergic activities. However, these compounds significantly differ from the compounds of the present invention in their types of substituents and sites of the substitution. Further this document also fails to disclose specific biological activities.
Journal of Medicinal Chemistry, 28, 298-302, 1985 discloses that PCA reaction is suppressed in rat by a 6-oxo-6H-imidazo[4,5,1-ij]quinoline-4-carboxylic acid derivative. However, it is also disclosed in this document that this compound simultaneously proved to be toxic to kidney. The compound of this document differs from the compounds of the present invention in its structure. This document also fails to refer to the activity of inhibiting the IgE antibody production.
There are known many other compounds that have the nitrogen-containing tricyclic skeleton identical with that of the compound of the present invention. However, no report has so far indicated the anti-allergic activity.
Among a variety of therapeutic agents for allergic diseases that have been developed, compounds disclosed in Japanese Patent Application Laid-Open (Kokai) Nos. 59(1984)-167564, 1(1989)-149784, 2(1990)-25906, and the like are known to have been developed from the view point of inhibiting the IgE antibody production. In the specification of some of these compounds, there are disclosures that some compounds inhibited the production of IgE antibody in some model animals. However, the degrees of the inhibitions are not quite sufficient, and none of such compounds have so far been used as a commercial pharmaceutical agent, yet.